Malignant progression and the effectiveness of cancer therapy are strongly modulated by innate and adaptive immunity4,33. Whereas myeloid cells and their inflammatory cytokines promote tumorigenesis and confer therapy resistance21,33, B and T lymphocytes exert both pro- and anti-tumorigenic effects7,34,35. Three different strategies can unleash the powerful anti-cancer activity of tumor-infiltrating T (TIL) cells: immune checkpoint inhibitors36,37, adoptive T cell therapy38, and, in part, immunogenic chemotherapy1,4.
Cancer is characterized by multiple genetic alterations and loss of normal cellular regulatory processes. This results in expression of tumor antigens, which can be presented by MHC molecules to activate T cells1,2. However, the microenvironment of advanced tumors establishes T cell tolerance, which contributes to malignant progression. Despite significant progress in understanding how T cell tolerance is implemented and maintained1,3, the critical rate-limiting mechanism operating in each cancer type remains unknown. Cancer-specific T cells must infiltrate and undergo activation within the tumor microenvironment, otherwise they cannot eradicate the malignancy. Indeed, new therapeutics that overcome tolerogenic mechanisms are effective in certain human cancers1. Immune mechanisms also affect the outcome of chemotherapy4. Importantly, certain chemotherapeutic agents (oxaliplatin, antracyclines) stimulate cancer-specific immune responses by either inducing immunogenic cell death (ICD) or immune effector mechanisms5,6. For example, in castrate-resistant prostate cancer (CRPC), B lymphocytes that are recruited by CXCL13 into prostate tumors promote development of CRPC that resists androgen ablation therapy, in a manner dependent on activation of an IKKα-Bmi1 module, needed for survival and proliferation of prostate cancer (PC) progenitor cells, by lymphotoxin (LT) expressing B cell7,8.
Thus, what is needed are methods for treating tumors and reducing tolerance to cancer chemotherapy, which otherwise contributes to malignant progression.